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Derakhshandeh N, Nazifi S, Mogheiseh A, Divar MR, Dadvand Z, Karimizadeh MS, Zeidabadi M. Oral nicotinic acid administration effect on lipids, thyroid hormones, and oxidative stress in intact adult dogs. BMC Vet Res 2025; 21:142. [PMID: 40038732 DOI: 10.1186/s12917-025-04597-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 02/11/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Nicotinic acid (niacin, Vitamin B3) is one of the most effective medicines for improving high-density lipoprotein concentrations. Obesity and related diseases are life-threatening to dogs. This study investigated the niacin effect on triglyceride, cholesterol, lipoproteins, thyroid hormones, oxidative stress, and lipid peroxidation in intact adult dogs. Blood samples were taken from seven healthy, intact adult dogs as a control group (day 0). Then, the animals received 1000 mg/dog of oral nicotinic acid tab daily for 42 days, and blood sampling was performed on days 14, 28, 42, and 56. RESULT The results showed an increasing trend in high-density lipoprotein (HDL) concentration. The highest HDL concentration (138.85 ± 43.72 mg/dl) was related to day 56; the HDL level followed a statistically significant increase between day 14 and 56. Unlike HDL, there was a decreasing trend in low-density lipoprotein (LDL) concentration. The lowest LDL concentration (21.85 ± 18.60 mg/dl) was related to day 56. The concentration of apolipoprotein A-I (apoA1) was significantly increased during the study. The highest concentration of apoA1 (1.66 ± 0.06 g/l) was on day 42. There was a significant increase in apoA1 concentrations between days 0 and 14, 42, and 56. The apoA1 was significantly increased between days 14 and 42 and 56. The apoA1 followed a statistically significant increase between days 28 and 42. Changes in thyroid hormone levels did not show any constant increasing or decreasing trend. On day 14, a decreasing trend in the concentrations of TT4, FT4, and T3 was observed. However, an increasing trend was detected in the concentrations of TT4, FT4, and T3 on days 28 and 42. However, the increase in the concentrations of TT4 and FT4 was less than that on day 0. After treatment (day 56), a decreasing trend was observed in thyroid hormone concentrations. The negative correlation was detected between apoA1 and triiodothyronine (T3), total thyroxine T4 (TT4)), and free T4 (FT4) concentrations on day 42. Furthermore, a significant negative relationship was observed between HDL and T4 on day 42. However, the relationship between triglyceride and T3 was statistically positive on day 14. There was an increasing trend in serum total antioxidant capacity (TAC). The highest TAC concentration (3.83 ± 0.62 µmol /l) was on day 56; however, the malondialdehyde (MDA) concentration was decreased during the study. The total antioxidant level followed a statistically significant increase between days 0 and 56 compared to days 14 and 42. CONCLUSION The study demonstrated the efficacy of nicotinic acid in improving serum HDL, apoA1, and TAC, as well as decreasing serum MDA and LDL concentrations.
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Affiliation(s)
- Nooshin Derakhshandeh
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O.Box: 7144169115, Shiraz, Fars, Iran.
| | - Saeed Nazifi
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O.Box: 7144169115, Shiraz, Fars, Iran
| | - Asghar Mogheiseh
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O.Box: 7144169115, Shiraz, Fars, Iran
| | - Mohammad Reza Divar
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O.Box: 7144169115, Shiraz, Fars, Iran
| | - Zahra Dadvand
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O.Box: 7144169115, Shiraz, Fars, Iran
| | - Mohammad Sadegh Karimizadeh
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O.Box: 7144169115, Shiraz, Fars, Iran
| | - Mahboobeh Zeidabadi
- Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, P.O.Box: 7144169115, Shiraz, Fars, Iran
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Jain A, Mishra AK, Hurkat P, Shilpi S, Mody N, Jain SK. Navigating liver cancer: Precision targeting for enhanced treatment outcomes. Drug Deliv Transl Res 2025:10.1007/s13346-024-01780-x. [PMID: 39847205 DOI: 10.1007/s13346-024-01780-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/24/2025]
Abstract
Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.
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Affiliation(s)
- Ankit Jain
- Department of Pharmacy, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
| | - Ashwini Kumar Mishra
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra, 425405, India
- Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, 284003, India
| | - Pooja Hurkat
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
| | - Satish Shilpi
- School of Pharmaceuticals and Population Health Informatics, FOP, DIT University, Dehradun, Uttarakahnad, India
| | - Nishi Mody
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
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Ding W, Sun Y, Han Y, Liu Y, Jin S. Transcriptome comparison revealed the difference in subcutaneous fat metabolism of Qinghai yak under different feeding conditions. PLoS One 2024; 19:e0311224. [PMID: 39637129 PMCID: PMC11620555 DOI: 10.1371/journal.pone.0311224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 09/16/2024] [Indexed: 12/07/2024] Open
Abstract
In order to explore the differences in subcutaneous fat metabolism and pathway information in yaks under different feeding conditions, this experiment used Illumina high-throughput sequencing technology to sequence the transcriptome of subcutaneous fat tissues of yaks under different feeding conditions and analyzed them bioinformatically. 9 naturally grazed yaks at 18 months of age were randomly divided into 3 groups, one group (G18_SF) was slaughtered, one group (G24_SF) continued to graze until 24 months of age was slaughtered, and one group (F24_SF) was housed until 24 months of age was slaughtered, and subcutaneous fat tissue was collected from the back of the yaks. A total of 15,261 expressed genes were identified in the nine samples, with 13,959 coexpressed genes and 533 differential expressed genes (DEGs), G18_SF vs F24_SF 133 DEGs, G18_SF vs G24_SF 469 DEGs, F24_SF vs G24_SF 5 DEGs. GO functional annotation analysis found that DEGs were mainly annotated in BP and CC, which included biological regulation, metabolic processes and cellular processes. KEGG revealed that the DEGs are mainly enriched for PPAR signaling pathway, AMPK signaling pathway and other pathways related to lipid metabolism. This study provides a scientific basis for further research on the effects of mRNA on subcutaneous fat in yaks under different feeding conditions.
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Affiliation(s)
- Weiqin Ding
- Academy of Animal Husbandry and Veterinary Sciences, Qinghai University, Xining, Qinghai, China
- Key Laboratory of Plateau Livestock Genetic Resources Protection and Innovative Utilization of Qinghai Provincial, Xining, Qinghai, China
| | - Yonggang Sun
- Academy of Animal Husbandry and Veterinary Sciences, Qinghai University, Xining, Qinghai, China
- Key Laboratory of Plateau Livestock Genetic Resources Protection and Innovative Utilization of Qinghai Provincial, Xining, Qinghai, China
| | - Yincang Han
- Academy of Animal Husbandry and Veterinary Sciences, Qinghai University, Xining, Qinghai, China
- Key Laboratory of Plateau Livestock Genetic Resources Protection and Innovative Utilization of Qinghai Provincial, Xining, Qinghai, China
| | - Yaqian Liu
- Academy of Animal Husbandry and Veterinary Sciences, Qinghai University, Xining, Qinghai, China
- Key Laboratory of Plateau Livestock Genetic Resources Protection and Innovative Utilization of Qinghai Provincial, Xining, Qinghai, China
| | - Shengwei Jin
- Academy of Animal Husbandry and Veterinary Sciences, Qinghai University, Xining, Qinghai, China
- Key Laboratory of Plateau Livestock Genetic Resources Protection and Innovative Utilization of Qinghai Provincial, Xining, Qinghai, China
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Becker AP, Biletch E, Kennelly JP, Julio AR, Villaneuva M, Nagari RT, Turner DW, Burton NR, Fukuta T, Cui L, Xiao X, Hong SG, Mack JJ, Tontonoz P, Backus KM. Lipid- and protein-directed photosensitizer proximity labeling captures the cholesterol interactome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.20.608660. [PMID: 39229057 PMCID: PMC11370482 DOI: 10.1101/2024.08.20.608660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
The physical properties of cellular membranes, including fluidity and function, are influenced by protein and lipid interactions. In situ labeling chemistries, most notably proximity-labeling interactomics are well suited to characterize these dynamic and often fleeting interactions. Established methods require distinct chemistries for proteins and lipids, which limits the scope of such studies. Here we establish a singlet-oxygen-based photocatalytic proximity labeling platform (POCA) that reports intracellular interactomes for both proteins and lipids with tight spatiotemporal resolution using cell-penetrant photosensitizer reagents. Using both physiologically relevant lipoprotein-complexed probe delivery and genetic manipulation of cellular cholesterol handling machinery, cholesterol-directed POCA captured established and unprecedented cholesterol binding proteins, including protein complexes sensitive to intracellular cholesterol levels and proteins uniquely captured by lipoprotein uptake. Protein-directed POCA accurately mapped known intracellular membrane complexes, defined sterol-dependent changes to the non-vesicular cholesterol transport protein interactome, and captured state-dependent changes in the interactome of the cholesterol transport protein Aster-B. More broadly, we find that POCA is a versatile interactomics platform that is straightforward to implement, using the readily available HaloTag system, and fulfills unmet needs in intracellular singlet oxygen-based proximity labeling proteomics. Thus, we expect widespread utility for POCA across a range of interactome applications, spanning imaging to proteomics.
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Affiliation(s)
- Andrew P. Becker
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA
| | - Elijah Biletch
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA
| | - John Paul Kennelly
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, Los Angeles, California 90095, USA
| | - Ashley R. Julio
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA
| | - Miranda Villaneuva
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA
- Molecular Biology Institute, UCLA, Los Angeles, California 90095, USA
| | - Rohith T. Nagari
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, Los Angeles, California 90095, USA
- Molecular Biology Institute, UCLA, Los Angeles, California 90095, USA
| | - Daniel W. Turner
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA
| | - Nikolas R. Burton
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA
| | - Tomoyuki Fukuta
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Liujuan Cui
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, Los Angeles, California 90095, USA
| | - Xu Xiao
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, Los Angeles, California 90095, USA
| | - Soon-Gook Hong
- Molecular Biology Institute, UCLA, Los Angeles, California 90095, USA
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
| | - Julia J. Mack
- Molecular Biology Institute, UCLA, Los Angeles, California 90095, USA
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
| | - Peter Tontonoz
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, Los Angeles, California 90095, USA
| | - Keriann M. Backus
- Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, USA
- Molecular Biology Institute, UCLA, Los Angeles, California 90095, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California 90095, USA
- Jonsson Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
- UCLA-DOE Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095, USA
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Zhang X, van der Vorst EPC. High-Density Lipoprotein Modifications: Causes and Functional Consequences in Type 2 Diabetes Mellitus. Cells 2024; 13:1113. [PMID: 38994965 PMCID: PMC11240616 DOI: 10.3390/cells13131113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/22/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024] Open
Abstract
High-density lipoprotein (HDL) is a group of small, dense, and protein-rich lipoproteins that play a role in cholesterol metabolism and various cellular processes. Decreased levels of HDL and HDL dysfunction are commonly observed in individuals with type 2 diabetes mellitus (T2DM), which is also associated with an increased risk for cardiovascular disease (CVD). Due to hyperglycemia, oxidative stress, and inflammation that develop in T2DM, HDL undergoes several post-translational modifications such as glycation, oxidation, and carbamylation, as well as other alterations in its lipid and protein composition. It is increasingly recognized that the generation of HDL modifications in T2DM seems to be the main cause of HDL dysfunction and may in turn influence the development and progression of T2DM and its related cardiovascular complications. This review provides a general introduction to HDL structure and function and summarizes the main modifications of HDL that occur in T2DM. Furthermore, the potential impact of HDL modifications on the pathogenesis of T2DM and CVD, based on the altered interactions between modified HDL and various cell types that are involved in glucose homeostasis and atherosclerotic plaque generation, will be discussed. In addition, some perspectives for future research regarding the T2DM-related HDL modifications are addressed.
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Affiliation(s)
- Xiaodi Zhang
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), 80336 Munich, Germany
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Zhang Y, Luo S, Gao Y, Tong W, Sun S. High-Density Lipoprotein Subfractions Remodeling: A Critical Process for the Treatment of Atherosclerotic Cardiovascular Diseases. Angiology 2024; 75:441-453. [PMID: 36788038 DOI: 10.1177/00033197231157473] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Numerous studies have shown that a low level of high-density lipoprotein cholesterol (HDL-C) is an independent biomarker of cardiovascular disease. High-density lipoprotein (HDL) is considered to be a protective factor for atherosclerosis (AS). Therefore, raising HDL-C has been widely recognized as a promising strategy to treat atherosclerotic cardiovascular diseases (ASCVD). However, several studies have found that increasing HDL-C levels does not necessarily reduce the risk of ASCVD. HDL particles are highly heterogeneous in structure, composition, and biological function. Moreover, HDL particles from atherosclerotic patients exhibit impaired anti-atherogenic functions and these dysfunctional HDL particles might even promote ASCVD. This makes it uncertain that HDL-raising therapy will prevent and treat ASCVD. It is necessary to comprehensively analyze the structure and function of HDL subfractions. We review current advances related to HDL subfractions remodeling and highlight how current lipid-modifying drugs such as niacin, statins, fibrates, and cholesteryl ester transfer protein inhibitors regulate cholesterol concentration of HDL and specific HDL subfractions.
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Affiliation(s)
- Yaling Zhang
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, China
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Shiyu Luo
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, China
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Yi Gao
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, China
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Wenjuan Tong
- Department of Gynecology and Obstetrics, First Affiliated Hospital, University of South China, Hengyang, China
| | - Shaowei Sun
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, China
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
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Raffin J, Rolland Y, Genoux A, Combes G, Croyal M, Perret B, Guyonnet S, Vellas B, Martinez LO, de Souto Barreto P. Associations between physical activity levels and ATPase inhibitory factor 1 concentrations in older adults. JOURNAL OF SPORT AND HEALTH SCIENCE 2024; 13:409-418. [PMID: 37748689 PMCID: PMC11116968 DOI: 10.1016/j.jshs.2023.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 05/19/2023] [Accepted: 08/28/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND Adenosine triphosphatase inhibitory factor 1 (IF1) is a key protein involved in energy metabolism. IF1 has been linked to various age-related diseases, although its relationship with physical activity (PA) remains unclear. Additionally, the apolipoprotein A-I (apoA-I), a PA-modulated lipoprotein, could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase. We examined here the associations between chronic PA and plasma IF1 concentrations among older adults, and we investigated whether apoA-I mediated these associations. METHODS In the present work, 1096 healthy adults (63.8% females) aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included. IF1 plasma concentrations (square root of ng/mL) were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial, while PA levels (square root of metabolic equivalent task min/week) were assessed using questionnaires administered each year from baseline to the 3-year visit. Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations. Mediation analyses were conducted to examine whether apoA-I mediated these associations. Mixed-effect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA. RESULTS Multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations (B = 0.021; SE = 0.010; p = 0.043). Mediation analyses revealed that about 37.7% of this relationship was mediated by apoA-I (Bab = 0.008; SE = 0.004; p = 0.023). Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years (time × IF1: B = -0.148; SE = 0.066; p = 0.025). CONCLUSION This study demonstrates that regular PA is associated with plasma IF1 concentrations, and it suggests that apoA-I partly mediates this association. Additionally, this study finds that baseline concentrations of IF1 can predict future changes in PA. However, further research is needed to fully understand the mechanisms underlying these observations.
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Affiliation(s)
- Jérémy Raffin
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31000, France.
| | - Yves Rolland
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31000, France; Centre d'Epidémiologie et de Recherche en Santé des Populations, Unité Mixte de Recherche 1295, Institut National de la Santé et de la Recherche Médicale, Université Toulouse-III-Paul-Sabatier, Toulouse 31000, France
| | - Annelise Genoux
- LimitAging Team, Institut des Maladies Métaboliques et Cardiovasculaires, Unité Mixte de Recherche 1297, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III - Paul Sabatier, Toulouse 31432, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31300, France
| | - Guillaume Combes
- LimitAging Team, Institut des Maladies Métaboliques et Cardiovasculaires, Unité Mixte de Recherche 1297, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III - Paul Sabatier, Toulouse 31432, France
| | - Mikael Croyal
- L'Institut du Thorax, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Centre Hospitalo-Universitaire de Nantes, Nantes Université, Nantes 44000, France; BioCore, US16, Structure Fédérative de Recherche Bonamy, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Centre Hospitalo-Universitaire de Nantes, Nantes Université, Nantes 44000, France; Plate-forme de spectrométrie de masse, Centre de Recherche en Nutrition HumaineOuest, Nantes 44000, France
| | - Bertrand Perret
- LimitAging Team, Institut des Maladies Métaboliques et Cardiovasculaires, Unité Mixte de Recherche 1297, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III - Paul Sabatier, Toulouse 31432, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31300, France
| | - Sophie Guyonnet
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31000, France; Centre d'Epidémiologie et de Recherche en Santé des Populations, Unité Mixte de Recherche 1295, Institut National de la Santé et de la Recherche Médicale, Université Toulouse-III-Paul-Sabatier, Toulouse 31000, France
| | - Bruno Vellas
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31000, France; Centre d'Epidémiologie et de Recherche en Santé des Populations, Unité Mixte de Recherche 1295, Institut National de la Santé et de la Recherche Médicale, Université Toulouse-III-Paul-Sabatier, Toulouse 31000, France
| | - Laurent O Martinez
- LimitAging Team, Institut des Maladies Métaboliques et Cardiovasculaires, Unité Mixte de Recherche 1297, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III - Paul Sabatier, Toulouse 31432, France.
| | - Philipe de Souto Barreto
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31000, France; Centre d'Epidémiologie et de Recherche en Santé des Populations, Unité Mixte de Recherche 1295, Institut National de la Santé et de la Recherche Médicale, Université Toulouse-III-Paul-Sabatier, Toulouse 31000, France
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Li Y, Zhang M, Li Y, Shen Y, Wang X, Li X, Wang Y, Yu T, Lv J, Qin Y. Flagellar hook protein FlgE promotes macrophage activation and atherosclerosis by targeting ATP5B. Atherosclerosis 2024; 390:117429. [PMID: 38278062 DOI: 10.1016/j.atherosclerosis.2023.117429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 01/28/2024]
Abstract
BACKGROUND AND AIMS Pseudomonas aeruginosa (P. aeruginosa) infections are strongly linked to the development of cardiovascular disease and atherosclerosis; however, the underlying mechanisms remain unclear. We previously confirmed that the flagellar hook protein FlgE in P. aeruginosa has immunostimulatory effects. This study investigated the effects and mechanisms of action of FlgE on atherogenesis. METHODS ApoE-/- mice were intravenously challenged with FlgE or FlgEM recombinant proteins for eight weeks. A murine model of chronic lung colonization was established using beads containing either mutable- or wild-type bacteria. Aortic sinus sections were stained to assess atherosclerosis progression. THP-1 macrophages exposed to FlgE or FlgEM were evaluated for their effects on lipid uptake and inflammation in vitro. Western blotting and pull-down assays were used to identify the binding proteins and signaling pathways involved, and specific blocking experiments were performed to confirm these effects. RESULTS FlgE accelerated atherosclerosis progression by triggering lipid deposition and inflammatory responses in high-fat diet (HFD)-fed ApoE-/- mice. In comparison to infection with wild-type PAO1, infection with PAO1/flgEΔBmF resulted in reduced atherosclerosis. Mechanistic analysis indicated that FlgE exacerbated lipoprotein uptake and foam cell formation by upregulating SR-A1 expression. Moreover, FlgE activated NF-κB and MAPK signaling, which subsequently led to inflammatory responses in THP-1-derived macrophages. Pull-down assays revealed that FlgE directly interacted with ATP5B, whereas blocking ATP5B attenuated FlgE-induced responses in macrophages. CONCLUSIONS FlgE induces macrophage lipid uptake and pro-inflammatory responses mediated by ATP5B/NF-kB/AP-1 signaling, which eventually results in atherosclerosis. These findings support the development of therapeutic strategies for P. aeruginosa infection-induced atherosclerosis.
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Affiliation(s)
- Yuanyuan Li
- Department of Laboratory Examination, People's Hospital of Rizhao City, The Affiliated Hospital of Jining Medical College, Rizhao, China
| | - Min Zhang
- Department of Laboratory Examination, People's Hospital of Rizhao City, The Affiliated Hospital of Jining Medical College, Rizhao, China
| | - Yanmeng Li
- Department of Laboratory Examination, People's Hospital of Rizhao City, The Affiliated Hospital of Jining Medical College, Rizhao, China
| | - Ying Shen
- National Clinical Research Center for Hematologic Disease, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou Medical College, Suchow University, Suzhou, 215006, China
| | - Xiaoping Wang
- Department of Laboratory Examination, People's Hospital of Rizhao City, The Affiliated Hospital of Jining Medical College, Rizhao, China
| | - Xiaolu Li
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, 266000, China
| | - Yiqiang Wang
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, 215123, China
| | - Tao Yu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao, 266000, China.
| | - Jie Lv
- Department of Laboratory Examination, People's Hospital of Rizhao City, The Affiliated Hospital of Jining Medical College, Rizhao, China.
| | - Yan Qin
- Department of Laboratory Examination, People's Hospital of Rizhao City, The Affiliated Hospital of Jining Medical College, Rizhao, China.
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9
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Manandhar B, Pandzic E, Deshpande N, Chen SY, Wasinger VC, Kockx M, Glaros EN, Ong KL, Thomas SR, Wilkins MR, Whan RM, Cochran BJ, Rye KA. ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin. Arterioscler Thromb Vasc Biol 2024; 44:e20-e38. [PMID: 38095105 DOI: 10.1161/atvbaha.123.319378] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 11/13/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND High cholesterol levels in pancreatic β-cells cause oxidative stress and decrease insulin secretion. β-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves β-cell insulin secretion by reducing oxidative stress. METHODS Ins-1E cells were cholesterol-loaded by incubation with cholesterol-methyl-β-cyclodextrin. Insulin secretion in the presence of 2.8 or 25 mmol/L glucose was quantified by radioimmunoassay. Internalization of fluorescently labeled apoA-I by β-cells was monitored by flow cytometry. The effects of apoA-I internalization on β-cell gene expression were evaluated by RNA sequencing. ApoA-I-binding partners on the β-cell surface were identified by mass spectrometry. Mitochondrial oxidative stress was quantified in β-cells and isolated islets with MitoSOX and confocal microscopy. RESULTS An F1-ATPase β-subunit on the β-cell surface was identified as the main apoA-I-binding partner. β-cell internalization of apoA-I was time-, concentration-, temperature-, cholesterol-, and F1-ATPase β-subunit-dependent. β-cells with internalized apoA-I (apoA-I+ cells) had higher cholesterol and cell surface F1-ATPase β-subunit levels than β-cells without internalized apoA-I (apoA-I- cells). The internalized apoA-I colocalized with mitochondria and was associated with reduced oxidative stress and increased insulin secretion. The IF1 (ATPase inhibitory factor 1) attenuated apoA-I internalization and increased oxidative stress in Ins-1E β-cells and isolated mouse islets. Differentially expressed genes in apoA-I+ and apoA-I- Ins-1E cells were related to protein synthesis, the unfolded protein response, insulin secretion, and mitochondrial function. CONCLUSIONS These results establish that β-cells are functionally heterogeneous, and apoA-I restores insulin secretion in β-cells with elevated cholesterol levels by improving mitochondrial redox balance.
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Affiliation(s)
- Bikash Manandhar
- School of Biomedical Sciences, Faculty of Medicine (B.M., E.N.G., K.L.O., S.R.T., B.J.C., K.-A.R.), UNSW, Sydney, Australia
| | - Elvis Pandzic
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre (E.P., R.M.W.), UNSW, Sydney, Australia
| | - Nandan Deshpande
- School of Biotechnology and Biomolecular Sciences (N.D., S.-Y.C., M.R.W.), UNSW, Sydney, Australia
| | - Sing-Young Chen
- School of Biotechnology and Biomolecular Sciences (N.D., S.-Y.C., M.R.W.), UNSW, Sydney, Australia
| | - Valerie C Wasinger
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre (V.C.W.), UNSW, Sydney, Australia
| | - Maaike Kockx
- ANZAC Research Institute, Concord, Sydney, Australia (M.K.)
| | - Elias N Glaros
- School of Biomedical Sciences, Faculty of Medicine (B.M., E.N.G., K.L.O., S.R.T., B.J.C., K.-A.R.), UNSW, Sydney, Australia
| | - Kwok Leung Ong
- School of Biomedical Sciences, Faculty of Medicine (B.M., E.N.G., K.L.O., S.R.T., B.J.C., K.-A.R.), UNSW, Sydney, Australia
| | - Shane R Thomas
- School of Biomedical Sciences, Faculty of Medicine (B.M., E.N.G., K.L.O., S.R.T., B.J.C., K.-A.R.), UNSW, Sydney, Australia
| | - Marc R Wilkins
- School of Biotechnology and Biomolecular Sciences (N.D., S.-Y.C., M.R.W.), UNSW, Sydney, Australia
| | - Renee M Whan
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre (E.P., R.M.W.), UNSW, Sydney, Australia
| | - Blake J Cochran
- School of Biomedical Sciences, Faculty of Medicine (B.M., E.N.G., K.L.O., S.R.T., B.J.C., K.-A.R.), UNSW, Sydney, Australia
| | - Kerry-Anne Rye
- School of Biomedical Sciences, Faculty of Medicine (B.M., E.N.G., K.L.O., S.R.T., B.J.C., K.-A.R.), UNSW, Sydney, Australia
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10
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Xia X, Liu L, Cai K, Song X, Yue W, Wang J. A splicing site change between exon 5 and 6 of the nuclear-encoded chloroplast-localized HvYGL8 gene results in reduced chlorophyll content and plant height in barley. FRONTIERS IN PLANT SCIENCE 2023; 14:1327246. [PMID: 38192692 PMCID: PMC10773589 DOI: 10.3389/fpls.2023.1327246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 11/30/2023] [Indexed: 01/10/2024]
Abstract
The chloroplast is an important cellular organelle and metabolic hub, which is not only responsible for plant photosynthesis but is also involved in the de novo biosynthesis of pigments, fatty acids, and hormone metabolisms. Several genes that are responsible for rice leaf color variations have been reported to be directly or indirectly involved in chlorophyll biosynthesis and chloroplast development, whereas a few genes have been functionally confirmed to be responsible for leaf color changes in barley at the molecular level. In this study, we obtained a yellow leaf and dwarf ygl8 mutant from the progeny of Morex (a variety of barley) seeds treated with EMS. We performed bulked-segregant analysis (BSA) and RNA-seq analysis and targeted a UMP kinase encoding gene, YGL8, which generated a splicing site change between exon 5 and 6 of YGL8 due to a G to A single-nucleotide transition in the 5th exon/intron junction in the ygl8 mutant. The splicing site change between exon 5 and 6 of YGL8 had no effects on chloroplast subcellular localization but resulted in an additional loop in the UMP kinase domain, which might disturb the access of the substrates. On one hand, the splicing site change between exon 5 and 6 of YGL8 downregulated the transcriptional expression of chloroplast-encoded genes and chlorophyll-biosynthesis-related genes in a temperature-dependent manner in the ygl8 mutant. On the other hand, the downregulation of bioactive GA-biosynthesis-related GA20ox genes and cell-wall-cellulose-biosynthesis-related CesA genes was also observed in the ygl8 mutant, which led to a reduction in plant height. Our study will facilitate the understanding of the regulation of leaf color and plant height in barley.
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Affiliation(s)
- Xue Xia
- Key Laboratory of Digital Dry Land Crops of Zhejiang Province, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
- Zhejiang Academy of Agricultural Sciences, National Barley Improvement Center, Hangzhou, China
- College of Advanced Agricultural Sciences, Zhejiang Agricultural and Forestry University, Hangzhou, China
| | - Lei Liu
- Key Laboratory of Digital Dry Land Crops of Zhejiang Province, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
- Zhejiang Academy of Agricultural Sciences, National Barley Improvement Center, Hangzhou, China
| | - Kangfeng Cai
- Key Laboratory of Digital Dry Land Crops of Zhejiang Province, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
- Zhejiang Academy of Agricultural Sciences, National Barley Improvement Center, Hangzhou, China
| | - Xiujuan Song
- Key Laboratory of Digital Dry Land Crops of Zhejiang Province, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
- Zhejiang Academy of Agricultural Sciences, National Barley Improvement Center, Hangzhou, China
- College of Advanced Agricultural Sciences, Zhejiang Agricultural and Forestry University, Hangzhou, China
| | - Wenhao Yue
- Key Laboratory of Digital Dry Land Crops of Zhejiang Province, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
- Zhejiang Academy of Agricultural Sciences, National Barley Improvement Center, Hangzhou, China
| | - Junmei Wang
- Key Laboratory of Digital Dry Land Crops of Zhejiang Province, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
- Zhejiang Academy of Agricultural Sciences, National Barley Improvement Center, Hangzhou, China
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11
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Zhang D, Jiang Y, Dong Y, Fu L, Zhuang L, Wu K, Dou X, Xu B, Wang C, Gong J. siRNA targeting Atp5a1 gene encoding ATPase α, the ligand of Peg fimbriae, reduced Salmonella Enteritidis adhesion. Avian Pathol 2023; 52:412-419. [PMID: 37526573 DOI: 10.1080/03079457.2023.2243842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/20/2023] [Accepted: 07/31/2023] [Indexed: 08/02/2023]
Abstract
Salmonella enterica serovar Enteritidis (S. Enteritidis) is a zoonotic pathogen that can infect both humans and animals. Among the 13 types of fimbrial operons in S. Enteritidis, the highly conserved Peg fimbriae play a crucial role in the adhesion and invasion of S. Enteritidis into host cells but are not well studied. In this study, we identified the ATP synthase subunit alpha (ATPase α) as a ligand of Peg fimbriae using ligand blotting and mass spectrometry techniques. We confirmed the in vitro binding of ATPase α to the purified adhesion protein (PegD). Furthermore, we used siRNA to suppress the expression of ATPase α gene Atp5a1 in Leghorn male hepatoma (LMH) cells, which resulted in a significant reduction in the adhesion rate of S. Enteritidis to the cells (P < 0.05). The findings in this study provide insight into the mechanism of S. Enteritidis infection through Peg fimbriae and highlight the importance of ATPase α in the adhesion process.RESEARCH HIGHLIGHTS Ligand blotting was performed to screen the ligand of S. Enteritidis Peg fimbriae.Binding assay confirmed that ATPase α is the ligand of the Peg fimbriae.siRNA targeting ATPase α gene (Atp5a1) significantly reduced S. Enteritidis adhesion.
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Affiliation(s)
- Di Zhang
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, People's Republic of China
| | - Yi Jiang
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, People's Republic of China
| | - Yongyi Dong
- Jiangsu Animal Disease Prevention and Control Center, Nanjing, People's Republic of China
| | - Lixia Fu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Republic of China
| | - Linlin Zhuang
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, People's Republic of China
| | - Kun Wu
- Jiangsu Animal Disease Prevention and Control Center, Nanjing, People's Republic of China
| | - Xinhong Dou
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, People's Republic of China
| | - Bu Xu
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, People's Republic of China
| | - Chengming Wang
- Department of Pathobiology, Auburn University College of Veterinary Medicine, Auburn, AL, USA
| | - Jiansen Gong
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, People's Republic of China
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12
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Banks WA. Viktor Mutt lecture: Peptides can cross the blood-brain barrier. Peptides 2023; 169:171079. [PMID: 37598757 DOI: 10.1016/j.peptides.2023.171079] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/16/2023] [Accepted: 08/16/2023] [Indexed: 08/22/2023]
Abstract
The field of peptides exploded in the 1970's and has continued to be a major area of discovery. Among the early discoveries was that peptides administered peripherally could affect brain functions. This led Kastin to propose that peptides could cross the blood-brain barrier (BBB). Although initially very controversial, Kastin, I, and others demonstrated not only that peptides can cross the BBB, but elucidated many fundamental characteristics of that passage. That work was in large part the basis of the 2022 Viktor Mutt Lectureship. Here, we review some of the early work with current updates on topics related to the penetration of peptides across the BBB. We briefly review mechanisms by which peripherally administered peptides can affect brain function without crossing the BBB, and then review the major mechanisms by which peptides and their analogs have been show to cross the BBB: transmembrane diffusion, saturable transport, and adsorptive transcytosis. Saturable transport systems are adaptable to physiologic changes and can be altered by disease states. In particular, the transport across the BBB of insulin and of pituitary adenylate cyclase activating polypeptide (PACAP) illustrate many of the concepts regarding peptide transport across the BBB.
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Affiliation(s)
- William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle 98108, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
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13
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Kao YC, Chang YW, Lai CP, Chang NW, Huang CH, Chen CS, Huang HC, Juan HF. Ectopic ATP synthase stimulates the secretion of extracellular vesicles in cancer cells. Commun Biol 2023; 6:642. [PMID: 37322056 PMCID: PMC10272197 DOI: 10.1038/s42003-023-05008-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 06/01/2023] [Indexed: 06/17/2023] Open
Abstract
ABSTARCT Ectopic ATP synthase on the plasma membrane (eATP synthase) has been found in various cancer types and is a potential target for cancer therapy. However, whether it provides a functional role in tumor progression remains unclear. Here, quantitative proteomics reveals that cancer cells under starvation stress express higher eATP synthase and enhance the production of extracellular vesicles (EVs), which are vital regulators within the tumor microenvironment. Further results show that eATP synthase generates extracellular ATP to stimulate EV secretion by enhancing P2X7 receptor-triggered Ca2+ influx. Surprisingly, eATP synthase is also located on the surface of tumor-secreted EVs. The EVs-surface eATP synthase increases the uptake of tumor-secreted EVs in Jurkat T-cells via association with Fyn, a plasma membrane protein found in immune cells. The eATP synthase-coated EVs uptake subsequently represses the proliferation and cytokine secretion of Jurkat T-cells. This study clarifies the role of eATP synthase on EV secretion and its influence on immune cells.
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Affiliation(s)
- Yi-Chun Kao
- Department of Life Science, National Taiwan University, Taipei, 106, Taiwan
| | - Yi-Wen Chang
- Department of Life Science, National Taiwan University, Taipei, 106, Taiwan
| | - Charles P Lai
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan
| | - Nai-Wen Chang
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Chen-Hao Huang
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 106, Taiwan
| | - Chien-Sheng Chen
- Department of Food Safety / Hygiene and Risk Management, National Cheng Kung University, Tainan, Taiwan
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
| | - Hsueh-Fen Juan
- Department of Life Science, National Taiwan University, Taipei, 106, Taiwan.
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan.
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 106, Taiwan.
- Center for Computational and Systems Biology, National Taiwan University, Taipei, 106, Taiwan.
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14
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Chang YW, Tony Yang T, Chen MC, Liaw YG, Yin CF, Lin-Yan XQ, Huang TY, Hou JT, Hung YH, Hsu CL, Huang HC, Juan HF. Spatial and temporal dynamics of ATP synthase from mitochondria toward the cell surface. Commun Biol 2023; 6:427. [PMID: 37072500 PMCID: PMC10113393 DOI: 10.1038/s42003-023-04785-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 03/30/2023] [Indexed: 04/20/2023] Open
Abstract
Ectopic ATP synthase complex (eATP synthase), located on cancer cell surface, has been reported to possess catalytic activity that facilitates the generation of ATP in the extracellular environment to establish a suitable microenvironment and to be a potential target for cancer therapy. However, the mechanism of intracellular ATP synthase complex transport remains unclear. Using a combination of spatial proteomics, interaction proteomics, and transcriptomics analyses, we find ATP synthase complex is first assembled in the mitochondria and subsequently delivered to the cell surface along the microtubule via the interplay of dynamin-related protein 1 (DRP1) and kinesin family member 5B (KIF5B). We further demonstrate that the mitochondrial membrane fuses to the plasma membrane in turn to anchor ATP syntheses on the cell surface using super-resolution imaging and real-time fusion assay in live cells. Our results provide a blueprint of eATP synthase trafficking and contribute to the understanding of the dynamics of tumor progression.
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Grants
- 109-2221-E-010-012-MY3 Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MOST 109-2221-E-010-011-MY3 Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MOST 109-2327-B-006-004 Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MOST 109-2320-B-002-017-MY3 Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MOST 109-2221-E-002-161-MY3 Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- NTU-110L8808 Ministry of Education (Ministry of Education, Republic of China (Taiwan))
- NTU-CC-109L104702-2 Ministry of Education (Ministry of Education, Republic of China (Taiwan))
- NTU-110L7103 Ministry of Education (Ministry of Education, Republic of China (Taiwan))
- NTU-111L7107 Ministry of Education (Ministry of Education, Republic of China (Taiwan))
- NTU-CC-112L892102 Ministry of Education (Ministry of Education, Republic of China (Taiwan))
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Affiliation(s)
- Yi-Wen Chang
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - T Tony Yang
- Department of Electrical Engineering, National Taiwan University, Taipei, 106, Taiwan
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 106, Taiwan
| | - Min-Chun Chen
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Y-Geh Liaw
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Chieh-Fan Yin
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Xiu-Qi Lin-Yan
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Ting-Yu Huang
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Jen-Tzu Hou
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Yi-Hsuan Hung
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
| | - Chia-Lang Hsu
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
| | - Hsueh-Fen Juan
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 106, Taiwan.
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 106, Taiwan.
- Center for Computational and Systems Biology, National Taiwan University, Taipei, 106, Taiwan.
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15
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Prothymosin α Plays Role as a Brain Guardian through Ecto-F 1 ATPase-P2Y 12 Complex and TLR4/MD2. Cells 2023; 12:cells12030496. [PMID: 36766838 PMCID: PMC9914670 DOI: 10.3390/cells12030496] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/21/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Prothymosin alpha (ProTα) was discovered to be a necrosis inhibitor from the conditioned medium of a primary culture of rat cortical neurons under starved conditions. This protein carries out a neuronal cell-death-mode switch from necrosis to apoptosis, which is, in turn, suppressed by a variety of neurotrophic factors (NTFs). This type of NTF-assisted survival action of ProTα is reproduced in cerebral and retinal ischemia-reperfusion models. Further studies that used a retinal ischemia-reperfusion model revealed that ProTα protects retinal cells via ecto-F1 ATPase coupled with the Gi-coupled P2Y12 receptor and Toll-like receptor 4 (TLR4)/MD2 coupled with a Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). In cerebral ischemia-reperfusion models, ProTα has additional survival mechanisms via an inhibition of matrix metalloproteases in microglia and vascular endothelial cells. Heterozygous or conditional ProTα knockout mice show phenotypes of anxiety, memory learning impairment, and a loss of neurogenesis. There are many reports that ProTα has multiple intracellular functions for cell survival and proliferation through a variety of protein-protein interactions. Overall, it is suggested that ProTα plays a key role as a brain guardian against ischemia stress through a cell-death-mode switch assisted by NTFs and a role of neurogenesis.
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16
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Singh V. F 1F o adenosine triphosphate (ATP) synthase is a potential drug target in non-communicable diseases. Mol Biol Rep 2023; 50:3849-3862. [PMID: 36715790 DOI: 10.1007/s11033-023-08299-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 01/19/2023] [Indexed: 01/31/2023]
Abstract
F1Fo adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes. F1Fo ATP synthase also regulates the central metabolic processes in the human body driven by proton motive force (Δp). Numerous studies have immensely contributed toward highlighting its regulation in improving energy homeostasis and maintaining mitochondrial integrity, which otherwise gets compromised in illnesses. Yet, its role in the implication of non-communicable diseases remains unknown. F1Fo ATP synthase dysregulation at gene level leads to reduced activity and delocalization in the cristae and plasma membranes, which is directly associated with non-communicable diseases: cardiovascular diseases, diabetes, neurodegenerative disorders, cancer, and renal diseases. Individual subunits of the F1Fo ATP synthase target ligand-based competitive or non-competitive inhibition. After performing a systematic literature review to understand its specific functions and its novel drug targets, the present article focuses on the central role of F1Fo ATP synthase in primary non-communicable diseases. Next, it discusses its involvement through various pathways and the effects of multiple inhibitors, activators, and modulators specific to non-communicable diseases with a futuristic outlook.
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Affiliation(s)
- Varsha Singh
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, 140401, India.
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17
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Ju X, Dong L, Ding Q. Hepatitis E Virus Life Cycle. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:141-157. [PMID: 37223864 DOI: 10.1007/978-981-99-1304-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) infects over 20 million people worldwide per year, leading to 30,000-40,000 deaths. In most cases HEV infection in a self-limited, acute illness. However, chronic infections could occur in immunocompromised individuals. Due to scarcity of robust cell culture models in vitro and genetic tractable animal models in vivo, the details of HEV life cycle, as well as its interaction with host cells still remain elusive, which dampens antivirals discovery. In this chapter, we present an update in the HEV infectious cycle steps: entry, genome replication/subgenomic RNA transcription, assembly, and release. Moreover, we discussed the future prospective on HEV research and illustrates important questions urgently to be addressed.
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Affiliation(s)
- Xiaohui Ju
- School of Medicine, Tsinghua University, Beijing, China
| | - Lin Dong
- School of Medicine, Tsinghua University, Beijing, China
| | - Qiang Ding
- School of Medicine, Tsinghua University, Beijing, China.
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18
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Pires Da Silva J, Wargny M, Raffin J, Croyal M, Duparc T, Combes G, Genoux A, Perret B, Vellas B, Guyonnet S, Thalamas C, Langin D, Moro C, Viguerie N, Rolland Y, Barreto PDS, Cariou B, Martinez LO. Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study. DIABETES & METABOLISM 2023; 49:101391. [PMID: 36174852 DOI: 10.1016/j.diabet.2022.101391] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/15/2022] [Accepted: 09/22/2022] [Indexed: 01/28/2023]
Abstract
AIM Mitochondrial dysfunction is associated with the development of type 2 diabetes mellitus (T2DM). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2DM. ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes. METHODS In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman's correlation coefficients, and the association with the risk of NOD was determined using Cox proportional-hazards models. RESULTS In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, P = 0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the body mass index (r = -0.20, P = 0.0005) and homeostasis model assessment of insulin resistance (HOMA-IR). (r = -0.37, P < 0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, P < 0.0001) and apoA-I (r = 0.33, P < 0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2DM after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], P = 0.012). CONCLUSION We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2DM.
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Affiliation(s)
- Julie Pires Da Silva
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Matthieu Wargny
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France; Nantes Université, CHU Nantes, Pôle Hospitalo-Universitaire 11 : Santé Publique, Clinique des données, INSERM, CIC 1413, F-44000 Nantes, France
| | - Jérémy Raffin
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France
| | - Mikaël Croyal
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France; Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, US16, SFR Bonamy, F-44000 Nantes, France; CRNH-Ouest Mass Spectrometry Core Facility, 44000 Nantes, France
| | - Thibaut Duparc
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Guillaume Combes
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Annelise Genoux
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France
| | - Bertrand Perret
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France
| | - Bruno Vellas
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Sophie Guyonnet
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Claire Thalamas
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Clinical Investigation Center, Université de Toulouse, INSERM, Université Toulouse III-Paul Sabatier, Toulouse University Hospitals, CIC1436, F-CRIN/FORCE Network, Toulouse, France
| | - Dominique Langin
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France; Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France; Institut Universitaire de France (IUF), Paris, France
| | - Cédric Moro
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Nathalie Viguerie
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France
| | - Yves Rolland
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Philipe de Souto Barreto
- Institut du Vieillissement, Gérontopôle de Toulouse, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP UMR 1295, University of Toulouse III, INSERM, UPS, Toulouse, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France
| | - Laurent O Martinez
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Université Toulouse III - Paul Sabatier (UPS), UMR1297, Toulouse, France.
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- Members are listed in the acknowledgements
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Vantaggiato L, Shaba E, Carleo A, Bezzini D, Pannuzzo G, Luddi A, Piomboni P, Bini L, Bianchi L. Neurodegenerative Disorder Risk in Krabbe Disease Carriers. Int J Mol Sci 2022; 23:13537. [PMID: 36362324 PMCID: PMC9654610 DOI: 10.3390/ijms232113537] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/26/2022] [Accepted: 10/30/2022] [Indexed: 11/09/2022] Open
Abstract
Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc -/-), heterozygous (galc +/-), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions.
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Affiliation(s)
- Lorenza Vantaggiato
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Enxhi Shaba
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Alfonso Carleo
- Department of Pulmonology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
| | - Daiana Bezzini
- Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Giovanna Pannuzzo
- Department of Biochemical and Biotechnological Sciences, Section of Physiology, University of Catania, 95121 Catania, Italy
| | - Alice Luddi
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
| | - Paola Piomboni
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
| | - Luca Bini
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Laura Bianchi
- Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, 53100 Siena, Italy
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20
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Ueda K, Suwanmanee Y. ATP5B Is an Essential Factor for Hepatitis B Virus Entry. Int J Mol Sci 2022; 23:ijms23179570. [PMID: 36076968 PMCID: PMC9455612 DOI: 10.3390/ijms23179570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Elucidation of the factors responsible for hepatitis B virus (HBV) is extremely important in order to understand the viral life cycle and pathogenesis, and thereby explore potential anti-HBV drugs. The recent determination that sodium taurocholate co-transporting peptide (NTCP) is an essential molecule for the HBV entry into cells led to the development of an HBV infection system in vitro using a human hepatocellular carcinoma (HCC) cell line expressing NTCP; however, the precise mechanism of HBV entry is still largely unknown, and thus it may be necessary to elucidate all the molecules involved. Here, we identified ATP5B as another essential factor for HBV entry. ATP5B was expressed on the cell surface of the HCC cell lines and bound with myristoylated but not with non-myristoylated preS1 2-47, which supported the notion that ATP5B is involved in the HBV entry process. Knockdown of ATP5B in NTCP-expressing HepG2 cells, which allowed HBV infection, reduced HBV infectivity with less cccDNA formation. Taken together, these results strongly suggested that ATP5B is an essential factor for HBV entry into the cells.
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21
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Decoding Functional High-Density Lipoprotein Particle Surfaceome Interactions. Int J Mol Sci 2022; 23:ijms23169506. [PMID: 36012766 PMCID: PMC9409371 DOI: 10.3390/ijms23169506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/10/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
High-density lipoprotein (HDL) is a mixture of complex particles mediating reverse cholesterol transport (RCT) and several cytoprotective activities. Despite its relevance for human health, many aspects of HDL-mediated lipid trafficking and cellular signaling remain elusive at the molecular level. During HDL’s journey throughout the body, its functions are mediated through interactions with cell surface receptors on different cell types. To characterize and better understand the functional interplay between HDL particles and tissue, we analyzed the surfaceome-residing receptor neighborhoods with which HDL potentially interacts. We applied a combination of chemoproteomic technologies including automated cell surface capturing (auto-CSC) and HATRIC-based ligand–receptor capturing (HATRIC-LRC) on four different cellular model systems mimicking tissues relevant for RCT. The surfaceome analysis of EA.hy926, HEPG2, foam cells, and human aortic endothelial cells (HAECs) revealed the main currently known HDL receptor scavenger receptor B1 (SCRB1), as well as 155 shared cell surface receptors representing potential HDL interaction candidates. Since vascular endothelial growth factor A (VEGF-A) was recently found as a regulatory factor of transendothelial transport of HDL, we next analyzed the VEGF-modulated surfaceome of HAEC using the auto-CSC technology. VEGF-A treatment led to the remodeling of the surfaceome of HAEC cells, including the previously reported higher surfaceome abundance of SCRB1. In total, 165 additional receptors were found on HAEC upon VEGF-A treatment representing SCRB1 co-regulated receptors potentially involved in HDL function. Using the HATRIC-LRC technology on human endothelial cells, we specifically aimed for the identification of other bona fide (co-)receptors of HDL beyond SCRB1. HATRIC-LRC enabled, next to SCRB1, the identification of the receptor tyrosine-protein kinase Mer (MERTK). Through RNA interference, we revealed its contribution to endothelial HDL binding and uptake. Furthermore, subsequent proximity ligation assays (PLAs) demonstrated the spatial vicinity of MERTK and SCRB1 on the endothelial cell surface. The data shown provide direct evidence for a complex and dynamic HDL receptome and that receptor nanoscale organization may influence binding and uptake of HDL.
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22
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Gatto C, Grandi M, Solaini G, Baracca A, Giorgio V. The F1Fo-ATPase inhibitor protein IF1 in pathophysiology. Front Physiol 2022; 13:917203. [PMID: 35991181 PMCID: PMC9389554 DOI: 10.3389/fphys.2022.917203] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/27/2022] [Indexed: 12/15/2022] Open
Abstract
The endogenous inhibitor of ATP synthase is a protein of about 10 kDa, known as IF1 which binds to the catalytic domain of the enzyme during ATP hydrolysis. The main role of IF1 consists of limiting ATP dissipation under condition of severe oxygen deprivation or in the presence of dysfunctions of mitochondrial respiratory complexes, causing a collapse in mitochondrial membrane potential and therefore ATP hydrolysis. New roles of IF1 are emerging in the fields of cancer and neurodegeneration. Its high expression levels in tumor tissues have been associated with different roles favouring tumor formation, progression and evasion. Since discordant mechanisms of action have been proposed for IF1 in tumors, it is of the utmost importance to clarify them in the prospective of defining novel approaches for cancer therapy. Other IF1 functions, including its involvement in mitophagy, may be protective for neurodegenerative and aging-related diseases. In the present review we aim to clarify and discuss the emerging mechanisms in which IF1 is involved, providing a critical view of the discordant findings in the literature.
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23
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Gore E, Duparc T, Genoux A, Perret B, Najib S, Martinez LO. The Multifaceted ATPase Inhibitory Factor 1 (IF1) in Energy Metabolism Reprogramming and Mitochondrial Dysfunction: A New Player in Age-Associated Disorders? Antioxid Redox Signal 2022; 37:370-393. [PMID: 34605675 PMCID: PMC9398489 DOI: 10.1089/ars.2021.0137] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: The mitochondrial oxidative phosphorylation (OXPHOS) system, comprising the electron transport chain and ATP synthase, generates membrane potential, drives ATP synthesis, governs energy metabolism, and maintains redox balance. OXPHOS dysfunction is associated with a plethora of diseases ranging from rare inherited disorders to common conditions, including diabetes, cancer, neurodegenerative diseases, as well as aging. There has been great interest in studying regulators of OXPHOS. Among these, ATPase inhibitory factor 1 (IF1) is an endogenous inhibitor of ATP synthase that has long been thought to avoid the consumption of cellular ATP when ATP synthase acts as an ATP hydrolysis enzyme. Recent Advances: Recent data indicate that IF1 inhibits ATP synthesis and is involved in a multitude of mitochondrial-related functions, such as mitochondrial quality control, energy metabolism, redox balance, and cell fate. IF1 also inhibits the ATPase activity of cell-surface ATP synthase, and it is used as a cardiovascular disease biomarker. Critical Issues: Although recent data have led to a paradigm shift regarding IF1 functions, these have been poorly studied in entire organisms and in different organs. The understanding of the cellular biology of IF1 is, therefore, still limited. The aim of this review was to provide an overview of the current understanding of the role of IF1 in mitochondrial functions, health, and diseases. Future Directions: Further investigations of IF1 functions at the cell, organ, and whole-organism levels and in different pathophysiological conditions will help decipher the controversies surrounding its involvement in mitochondrial function and could unveil therapeutic strategies in human pathology. Antioxid. Redox Signal. 37, 370-393.
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Affiliation(s)
- Emilia Gore
- I2MC, University of Toulouse, INSERM, UPS, Toulouse, France
| | - Thibaut Duparc
- I2MC, University of Toulouse, INSERM, UPS, Toulouse, France
| | - Annelise Genoux
- I2MC, University of Toulouse, INSERM, UPS, Toulouse, France.,Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France
| | - Bertrand Perret
- I2MC, University of Toulouse, INSERM, UPS, Toulouse, France.,Service de Biochimie, Pôle de biologie, Hôpital de Purpan, CHU de Toulouse, Toulouse, France
| | - Souad Najib
- I2MC, University of Toulouse, INSERM, UPS, Toulouse, France
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Gallinat A, Badimon L. DJ-1 interacts with the ectopic ATP-synthase in endothelial cells during acute ischemia and reperfusion. Sci Rep 2022; 12:12753. [PMID: 35882968 PMCID: PMC9325725 DOI: 10.1038/s41598-022-16998-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/19/2022] [Indexed: 01/28/2023] Open
Abstract
Endothelial cells (ECs) play a central role in ischemia. ATP-Synthase is now recognized to be ectopically expressed in the cell surface of many cell types, with putative roles described in angiogenesis, proliferation, and intracellular pH regulation. DJ-1 is a multifunctional protein, involved in cell protection against ischemia, ischemia–reperfusion (I/R), and oxidative stress, that regulates mitochondrial ATP-synthase. Here we focused on the characterization of the endothelial dynamics of DJ-1, and its implication in the regulation of the ectopic ATP-synthase (ecATP-S) activity, during acute ischemia and I/R in ECs. We found that DJ-1 is secreted from ECs, by a mechanism enhanced in ischemia and I/R. A cleaved form of DJ-1 (DJ-1∆C) was found only in the secretome of ischemic cells. The ecATP-S activity increased following acute ischemia in ECs, coinciding with DJ-1 and DJ-1∆C secretion. The inhibition of DJ-1 expression inhibited the ecATP-S response to ischemia by ∼ 50%, and its exogenous administration maximized the effect, together with an enhanced Akt phosphorylation and angiotube-formation potential at reperfusion. Immunoprecipitation studies showed direct interaction between DJ-1 and the ecATP-S. Altogether suggesting that DJ-1 is actively cleaved and released from ischemic ECs and plays an important role in the regulation of the ecATP-S activity during acute ischemia and reperfusion.
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Affiliation(s)
- Alex Gallinat
- Cardiovascular Program-ICCC, IR-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, c/Sant Antoni María Claret, 167, 08025, Barcelona, Spain.,Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Lina Badimon
- Cardiovascular Program-ICCC, IR-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, c/Sant Antoni María Claret, 167, 08025, Barcelona, Spain. .,CIBERCV-Instituto de Salud Carlos III, Madrid, Spain. .,UAB-Chair Cardiovascular Research, Barcelona, Spain.
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25
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Quantitative phosphoproteomics reveals ectopic ATP synthase on mesenchymal stem cells to promote tumor progression via ERK/c-Fos pathway activation. Mol Cell Proteomics 2022; 21:100237. [PMID: 35439648 PMCID: PMC9117939 DOI: 10.1016/j.mcpro.2022.100237] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 04/01/2022] [Accepted: 04/13/2022] [Indexed: 11/22/2022] Open
Abstract
The tumor microenvironment (TME), which comprises cellular and noncellular components, is involved in the complex process of cancer development. Emerging evidence suggests that mesenchymal stem cells (MSCs), one of the vital regulators of the TME, foster tumor progression through paracrine secretion. However, the comprehensive phosphosignaling pathways that are mediated by MSC-secreting factors have not yet been fully established. In this study, we attempt to dissect the MSC-triggered mechanism in lung cancer using quantitative phosphoproteomics. A total of 1958 phosphorylation sites are identified in lung cancer cells stimulated with MSC-conditioned medium. Integrative analysis of the identified phosphoproteins and predicted kinases demonstrates that MSC-conditioned medium functionally promotes the proliferation and migration of lung cancer via the ERK/phospho-c-Fos-S374 pathway. Recent studies have reported that extracellular ATP accumulates in the TME and stimulates the P2X7R on the cancer cell membrane via purinergic signaling. We observe that ectopic ATP synthase is located on the surface of MSCs and excreted extracellular ATP into the lung cancer microenvironment to trigger the ERK/phospho-c-Fos-S374 pathway, which is consistent with these previous findings. Our results suggest that ectopic ATP synthase on the surface of MSCs releases extracellular ATP into the TME, which promotes cancer progression via activation of the ERK/phospho-c-Fos-S374 pathway.
Mesenchymal stem cells (MSCs) enhance lung cancer development through extracellular factor secretion. Phosphoproteomics discover MSCs-regulated phosphosignaling in the lung cancer. Ectopic ATP synthase on MSCs surface produces ATP into the tumor microenvironment. MSC-secreted extracellular ATP mediates the phosphorylation of the ERK/c-Fos axis.
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The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology. Int J Mol Sci 2022; 23:ijms23115883. [PMID: 35682562 PMCID: PMC9180512 DOI: 10.3390/ijms23115883] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 12/19/2022] Open
Abstract
The endothelium plays a key role in blood vessel health. At the interface of the blood, it releases several mediators that regulate local processes that protect against the development of cardiovascular disease. In this interplay, there is increasing evidence for a role of extracellular nucleotides and endothelial purinergic P2Y receptors (P2Y-R) in vascular protection. Recent advances have revealed that endothelial P2Y1-R and P2Y2-R mediate nitric oxide-dependent vasorelaxation as well as endothelial cell proliferation and migration, which are processes involved in the regeneration of damaged endothelium. However, endothelial P2Y2-R, and possibly P2Y1-R, have also been reported to promote vascular inflammation and atheroma development in mouse models, with endothelial P2Y2-R also being described as promoting vascular remodeling and neointimal hyperplasia. Interestingly, at the interface with lipid metabolism, P2Y12-R has been found to trigger HDL transcytosis through endothelial cells, a process known to be protective against lipid deposition in the vascular wall. Better characterization of the role of purinergic P2Y-R and downstream signaling pathways in determination of the endothelial cell phenotype in healthy and pathological environments has clinical potential for the prevention and treatment of cardiovascular diseases.
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HDL as Bidirectional Lipid Vectors: Time for New Paradigms. Biomedicines 2022; 10:biomedicines10051180. [PMID: 35625916 PMCID: PMC9138557 DOI: 10.3390/biomedicines10051180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 02/06/2023] Open
Abstract
The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration.
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Sasaki S, Oba K, Kodera Y, Itakura M, Shichiri M. ANGT_HUMAN[448–462], an Anorexigenic Peptide Identified using Plasma Peptidomics. J Endocr Soc 2022; 6:bvac082. [PMID: 35702602 PMCID: PMC9184509 DOI: 10.1210/jendso/bvac082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Indexed: 11/19/2022] Open
Abstract
Abstract
The discovery of bioactive peptides is an important research target that enables the elucidation of the pathophysiology of human diseases and provides seeds for drug discovery. Using a large number of native peptides previously identified using plasma peptidomics technology, we sequentially synthesized selected sequences and subjected them to functional screening using human cultured cells. A 15-amino-acid residue proangiotensinogen-derived peptide, designated ANGT_HUMAN[448–462], elicited cellular responses and bound to cultured human cells. Synthetic fluorescent-labeled and biotinylated ANGT_HUMAN[448–462] peptides were rendered to bind to cell- and tissue-derived proteins and peptide-cell protein complexes were retrieved and analyzed using liquid chromatography-tandem mass spectrometry, revealing the β-subunit of ATP synthase as its cell-surface binding protein. Because ATP synthase mediates the effects of anorexigenic peptides, the ability of ANGT_HUMAN[448–462] to modulate eating behavior in mice was investigated. Both intraperitoneal and intracerebroventricular injections of low doses of ANGT_HUMAN[448–462] suppressed spontaneous food and water intake throughout the dark phase of the diurnal cycle without affecting locomotor activity. Immunoreactive ANGT_HUMAN[448–462], distributed throughout human tissues and in human-derived cells, is mostly co-localized with angiotensin II and is occasionally present separately from angiotensin II. In this study, an anorexigenic peptide, ANGT_HUMAN[448–462], was identified by exploring cell surface target proteins of the human native peptides identified using plasma peptidomics.
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Affiliation(s)
- Sayaka Sasaki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine Kanagawa 252-0374, Japan
| | - Kazuhito Oba
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine Kanagawa 252-0374, Japan
| | - Yoshio Kodera
- Department of Physics, Kitasato University School of Science, Kanagawa 252-0373, Japan
- Center for Disease Proteomics, Kitasato University School of Science, Kanagawa 252-0373, Japan
| | - Makoto Itakura
- Department of Biochemistry, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine Kanagawa 252-0374, Japan
- Department of Diabetes, Endocrinology and Metabolism, Tokyo Kyosai Hospital, Tokyo 153-8934, Japan
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MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation. Acta Pharmacol Sin 2022; 43:897-907. [PMID: 34316032 PMCID: PMC8976090 DOI: 10.1038/s41401-021-00729-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 06/27/2021] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is a common comorbidity in patients with cancer, and the main leading cause of noncancer-related deaths in cancer survivors. Considering that current antitumor drugs usually induce cardiovascular injury, the quest for developing new antitumor drugs, especially those with cardiovascular protection, is crucial for improving cancer prognosis. MK2206 is a phase II clinical anticancer drug and the role of this drug in cardiovascular disease is still unclear. Here, we revealed that MK2206 significantly reduced vascular inflammation, atherosclerotic lesions, and inhibited proliferation of vascular smooth muscle cell in ApoE-/- mice in vivo. We demonstrated that MK2206 reduced lipid accumulation by promoting cholesterol efflux but did not affect lipid uptake and decreased inflammatory response by modulating inflammation-related mRNA stability in macrophages. In addition, we revealed that MK2206 suppressed migration, proliferation, and inflammation in vascular smooth muscle cells. Moreover, MK2206 inhibited proliferation and inflammation of endothelial cells. The present results suggest that MK2206, as a promising drug in clinical antitumor therapy, exhibits anti-inflammatory and antiatherosclerotic potential. This report provides a novel strategy for the prevention of cardiovascular comorbidities in cancer survivors.
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Loh D, Reiter RJ. Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders. Antioxidants (Basel) 2021; 10:1483. [PMID: 34573116 PMCID: PMC8465482 DOI: 10.3390/antiox10091483] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid-liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.
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Affiliation(s)
- Doris Loh
- Independent Researcher, Marble Falls, TX 78654, USA
| | - Russel J. Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX 78229, USA
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31
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Meschi E, Delanoue R. Adipokine and fat body in flies: Connecting organs. Mol Cell Endocrinol 2021; 533:111339. [PMID: 34082046 DOI: 10.1016/j.mce.2021.111339] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 10/21/2022]
Abstract
Under conditions of nutritional and environmental stress, organismal homeostasis is preserved through inter-communication between multiple organs. To do so, higher organisms have developed a system of interorgan communication through which one tissue can affect the metabolism, activity or fate of remote organs, tissues or cells. In this review, we discuss the latest findings emphasizing Drosophila melanogaster as a powerful model organism to study these interactions and may constitute one of the best documented examples depicting the long-distance communication between organs. In flies, the adipose tissue appears to be one of the main organizing centers for the regulation of insect development and behavior: it senses nutritional and hormonal signals and in turn, orchestrates the release of appropriate adipokines. We discuss the nature and the role of recently uncovered adipokines, their regulations by external cues, their secretory routes and their modes of action to adjust developmental growth and timing accordingly. These findings have the potential for identification of candidate factors and signaling pathways that mediate conserved interorgan crosstalk.
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Affiliation(s)
- Eleonora Meschi
- Centre for Neural Circuit and Behaviour, University of Oxford, Mansfield road, OX3 1SR, Oxford, UK
| | - Renald Delanoue
- University Côte d'Azur, CNRS, Inserm, Institute of Biology Valrose Parc Valrose, 06108, Nice, France.
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Stasi A, Franzin R, Fiorentino M, Squiccimarro E, Castellano G, Gesualdo L. Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications. Int J Mol Sci 2021; 22:5980. [PMID: 34205975 PMCID: PMC8197836 DOI: 10.3390/ijms22115980] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.
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Affiliation(s)
- Alessandra Stasi
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Rossana Franzin
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Marco Fiorentino
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Enrico Squiccimarro
- Department of Emergency and Organ Transplant (DETO), University of Bari, 70124 Bari, Italy;
- Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre (MUMC), 6229HX Maastricht, The Netherlands
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy;
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
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33
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Dong X, Li Y, Li W, Kang W, Tang R, Wu W, Xing Z, Zhou L. The function of Cav-1 in MDA-MB-231 breast cancer cell migration and invasion induced by ectopic ATP5B. Med Oncol 2021; 38:73. [PMID: 34009483 PMCID: PMC8134283 DOI: 10.1007/s12032-021-01519-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 05/04/2021] [Indexed: 12/03/2022]
Abstract
Ectopic ATP5B, which is located in a unique type of lipid raft caveolar structure, can be upregulated by cholesterol loading. As the structural component of caveolae, Cav-1 is a molecular hub that is involved in transmembrane signaling. In a previous study, the ATP5B-specific binding peptide B04 was shown to inhibit the migration and invasion of prostate cancer cells, and the expression of ATP5B on the plasma membrane of MDA-MB-231 cells was confirmed. The present study investigated the effect of ectopic ATP5B on the migration and invasion of MDA-MB-231 cells and examined the involvement of Cav-1. Cholesterol loading increased the level of ectopic ATP5B and promoted cell migration and invasion. These effects were blocked by B04. Ectopic ATP5B was physically colocalized with Cav-1, as demonstrated by double immunofluorescence staining and coimmunoprecipitation. After Cav-1 knockdown, the migration and invasion abilities of MDA-MB-231 cells were significantly decreased, suggesting that Cav-1 influences the function of ectopic ATP5B. Furthermore, these effects were not reversed after treatment with cholesterol. We concluded that Cav-1 may participate in MDA-MB-231 cell migration and invasion induced by binding to ectopic ATP5B.
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Affiliation(s)
- Xinjie Dong
- Department of Pathology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Yilei Li
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Wei Li
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Wenzhe Kang
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Rong Tang
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Wenyi Wu
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Ziyi Xing
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China.
| | - Lijuan Zhou
- The Key Laboratory of Pathobiology, Ministry of Education, The College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China.
- Electron Microscopy Laboratory of Renal Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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Sharifian Gh M. Recent Experimental Developments in Studying Passive Membrane Transport of Drug Molecules. Mol Pharm 2021; 18:2122-2141. [PMID: 33914545 DOI: 10.1021/acs.molpharmaceut.1c00009] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The ability to measure the passive membrane permeation of drug-like molecules is of fundamental biological and pharmaceutical importance. Of significance, passive diffusion across the cellular membranes plays an effective role in the delivery of many pharmaceutical agents to intracellular targets. Hence, approaches for quantitative measurement of membrane permeability have been the topics of research for decades, resulting in sophisticated biomimetic systems coupled with advanced techniques. In this review, recent developments in experimental approaches along with theoretical models for quantitative and real-time analysis of membrane transport of drug-like molecules through mimetic and living cell membranes are discussed. The focus is on time-resolved fluorescence-based, surface plasmon resonance, and second-harmonic light scattering approaches. The current understanding of how properties of the membrane and permeant affect the permeation process is discussed.
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Affiliation(s)
- Mohammad Sharifian Gh
- Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22908, United States
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Tatsushima K, Hasuzawa N, Wang L, Hiasa M, Sakamoto S, Ashida K, Sudo N, Moriyama Y, Nomura M. Vesicular ATP release from hepatocytes plays a role in the progression of nonalcoholic steatohepatitis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166013. [PMID: 33212187 DOI: 10.1016/j.bbadis.2020.166013] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 11/03/2020] [Accepted: 11/09/2020] [Indexed: 12/18/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is becoming a growing public health problem along with the increase of metabolic syndrome worldwide. Extracellular nucleotides are known to serve as a danger signal by initiating purinergic signaling in many inflammatory disorders, although the role of purinergic signaling in the progression of NASH remains to be clarified. Vesicular nucleotide transporter (VNUT) is a key molecule responsible for vesicular ATP release to initiate purinergic signaling. Here, we studied the role of VNUT in the progression of nonalcoholic steatohepatitis. VNUT was expressed in mouse hepatocytes and associated, at least in part, with apolipoprotein B (apoB)-containing vesicles. High glucose stimulation evoked release of appreciable amount of ATP from hepatocytes, which disappeared in hepatocytes of Vnut knockout (Vnut-/-) mice. Glucose treatment also stimulated triglyceride secretion from hepatocytes, which was inhibited by PPADS and MRS211, antagonists of P2Y receptors, and clodronate, a VNUT inhibitor, and was significantly reduced in Vnut-/- mice. In vivo, postprandial secretion of triglyceride from hepatocytes was observed, while the serum triglyceride level was significantly reduced in Vnut-/- mice. On a high-fat diet, the liver of wild type mice exhibited severe inflammation, fibrosis, and macrophage infiltration, which is similar to NASH in humans, while this NASH pathology was not observed in Vnut-/- mice. These results suggest that VNUT-mediated vesicular ATP release regulates triglyceride secretion and involves in chronic inflammation in hepatocytes. Since blockade of vesicular ATP release protects against progression of steatohepatitis, VNUT may be a pharmacological target for NASH.
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Affiliation(s)
- Keita Tatsushima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Endocrine Center, Toranomon Hospital, Tokyo 105-8470, Japan
| | - Nao Hasuzawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Lixiang Wang
- Department of Medical Biochemistry, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Miki Hiasa
- Department of Membrane Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
| | - Shohei Sakamoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kenji Ashida
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Nobuyuki Sudo
- Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinori Moriyama
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; Department of Membrane Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
| | - Masatoshi Nomura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
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36
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Lin W, Qiao C, Hu J, Wei Q, Xu T. Conserved role of ATP synthase in mammalian cilia. Exp Cell Res 2021; 401:112520. [PMID: 33639177 DOI: 10.1016/j.yexcr.2021.112520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 02/09/2021] [Accepted: 02/11/2021] [Indexed: 10/22/2022]
Abstract
We previously found that ATP synthases localize to male-specific sensory cilia and control the ciliary response by regulating polycystin signalling in Caenorhabditis elegans. Herein, we discovered that the ciliary localization of ATP synthase is evolutionarily conserved in mammals. We showed that the ATP synthase subunit F1β is colocalized with the cilia marker acetylated α-tubulin in both mammalian renal epithelial cells (MDCK) and normal mouse cholangiocytes (NMCs). Treatment with ATP synthase inhibitor oligomycin impaired ciliogenesis in MDCK cells, and F1β was co-immunoprecipitated with PKD2 in mammalian cells. Our study provides evidence for the evolutionarily conserved localization of ATP synthase in cilia from worm to mammals. Defects in ATP synthase can lead to ciliary dysfunction, which may be a potential mechanism of polycystic kidney disease.
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Affiliation(s)
- Wenjun Lin
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Cheng Qiao
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Jinghua Hu
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Qing Wei
- Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, 518055, China
| | - Tao Xu
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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37
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Liu WJ, Chang YS, Chen PY, Wu SP. F1 ATP synthase β subunit is a putative receptor involved in white spot syndrome virus infection in shrimp by binding with viral envelope proteins VP51B and VP150. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 114:103810. [PMID: 32750398 DOI: 10.1016/j.dci.2020.103810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 06/11/2023]
Abstract
White spot syndrome virus (WSSV) is highly virulent toward shrimp, and F1 ATP synthase β subunit (ATPsyn-β) has been suggested to be involved in WSSV infection. Therefore, in this study, interactions between Penaeus monodon ATPsyn-β (PmATPsyn-β) and WSSV structural proteins were characterized. Based on the results of yeast two-hybrid, co-immunoprecipitation, and protein pull-down assays, WSSV VP51B and VP150 were identified as being able to interact with PmATPsyn-β. Membrane topology assay results indicated that VP51B and VP150 are envelope proteins with large portions exposed outside the WSSV virion. Cellular localization assay results demonstrated that VP51B and VP150 co-localize with PmATPsyn-β on the membranes of transfected cells. Enzyme-linked immunosorbent assay (ELISA) and competitive ELISA results demonstrated that VP51B and VP150 bound to PmATPsyn-β in a dose-dependent manner, which could be competitively inhibited by the addition of WSSV virions. In vivo neutralization assay results further showed that both recombinant VP51B and VP150 could delay mortality in shrimp challenged with WSSV.
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Affiliation(s)
- Wang-Jing Liu
- Department of Earth and Life Science, University of Taipei, Taipei, Taiwan.
| | - Yun-Shiang Chang
- Department of Biomedical Sciences, Da-Yeh University, Changhua, Taiwan
| | - Pin-Yu Chen
- Department of Earth and Life Science, University of Taipei, Taipei, Taiwan
| | - Shu-Ping Wu
- Department of Earth and Life Science, University of Taipei, Taipei, Taiwan
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A reference measurement of circulating ATPase inhibitory factor 1 (IF1) in humans by LC-MS/MS: Comparison with conventional ELISA. Talanta 2020; 219:121300. [DOI: 10.1016/j.talanta.2020.121300] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 11/17/2022]
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Pedrini S, Chatterjee P, Hone E, Martins RN. High‐density lipoprotein‐related cholesterol metabolism in Alzheimer’s disease. J Neurochem 2020; 159:343-377. [DOI: 10.1111/jnc.15170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/18/2020] [Accepted: 08/20/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Steve Pedrini
- Sarich Neurosciences Research InstituteEdith Cowan University Nedlands WA Australia
| | - Pratishtha Chatterjee
- Sarich Neurosciences Research InstituteEdith Cowan University Nedlands WA Australia
- Department of Biomedical Sciences Faculty of Medicine, Health and Human Sciences Macquarie University Sydney NSW Australia
| | - Eugene Hone
- Sarich Neurosciences Research InstituteEdith Cowan University Nedlands WA Australia
| | - Ralph N. Martins
- Sarich Neurosciences Research InstituteEdith Cowan University Nedlands WA Australia
- Department of Biomedical Sciences Faculty of Medicine, Health and Human Sciences Macquarie University Sydney NSW Australia
- School of Psychiatry and Clinical Neurosciences University of Western Australia Nedlands WA Australia
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40
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Chang YW, Hsu CL, Tang CW, Chen XJ, Huang HC, Juan HF. Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling Network. Mol Cell Proteomics 2020; 19:1805-1825. [PMID: 32788343 DOI: 10.1074/mcp.ra120.002219] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Indexed: 12/24/2022] Open
Abstract
The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIα and subsequently enhancing the phosphorylation level of topo IIα. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIα/GAS5 network in gefitinib-resistant lung cancer cells.
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Affiliation(s)
- Yi-Wen Chang
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan
| | - Chia-Lang Hsu
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Wei Tang
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan
| | - Xiang-Jun Chen
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
| | - Hsueh-Fen Juan
- Department of Life Science, Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
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Soppert J, Lehrke M, Marx N, Jankowski J, Noels H. Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting. Adv Drug Deliv Rev 2020; 159:4-33. [PMID: 32730849 DOI: 10.1016/j.addr.2020.07.019] [Citation(s) in RCA: 180] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022]
Abstract
With cardiovascular disease being the leading cause of morbidity and mortality worldwide, effective and cost-efficient therapies to reduce cardiovascular risk are highly needed. Lipids and lipoprotein particles crucially contribute to atherosclerosis as underlying pathology of cardiovascular disease and influence inflammatory processes as well as function of leukocytes, vascular and cardiac cells, thereby impacting on vessels and heart. Statins form the first-line therapy with the aim to block cholesterol synthesis, but additional lipid-lowering drugs are sometimes needed to achieve low-density lipoprotein (LDL) cholesterol target values. Furthermore, beyond LDL cholesterol, also other lipid mediators contribute to cardiovascular risk. This review comprehensively discusses low- and high-density lipoprotein cholesterol, lipoprotein (a), triglycerides as well as fatty acids and derivatives in the context of cardiovascular disease, providing mechanistic insights into their role in pathological processes impacting on cardiovascular disease. Also, an overview of applied as well as emerging therapeutic strategies to reduce lipid-induced cardiovascular burden is provided.
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Affiliation(s)
- Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Aachen, Germany
| | - Michael Lehrke
- Medical Clinic I, University Hospital Aachen, Aachen, Germany
| | - Nikolaus Marx
- Medical Clinic I, University Hospital Aachen, Aachen, Germany
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Aachen, Germany; Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht University, the Netherlands
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Aachen, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
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Serum level of HDL particles are independently associated with long-term prognosis in patients with coronary artery disease: The GENES study. Sci Rep 2020; 10:8138. [PMID: 32424189 PMCID: PMC7234989 DOI: 10.1038/s41598-020-65100-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/27/2020] [Indexed: 01/07/2023] Open
Abstract
HDL-Cholesterol (HDL-C) is not an accurate surrogate marker to measure the cardioprotective functions of HDL in coronary artery diseases (CAD) patients. Hence, measurement of other HDL-related parameters may have prognostic superiority over HDL-C. In this work, we examined the predictive value of HDL particles profile for long-term mortality in CAD patients and to compare its informative value to that of HDL-C and apoA-I. HDL particles profiles were measured by nuclear magnetic resonance (NMR) spectroscopy in 214 male participants with stable CAD (45-74 years). Median follow up was 12.5 years with a 36.4% mortality rate. Cardiovascular mortality accounted for 64.5%. Mean concentrations of total HDL particles (HDL-P), small-sized HDL (SHDL-P) and apoA-I were lower in deceased than in surviving patients whereas no difference was observed according to HDL-C and large HDL particles. All NMR-HDL measures were correlated between themselves and with other HDL markers (HDL-C, apoA-I and LpA-I). In a multivariate model adjusted for cardiovascular risk factors and bioclinical variables, HDL-P and SHDL-P displayed the strongest inverse association with all-cause and cardiovascular mortality. Weaker associations were recorded for apoA-I. Based on our results, we conclude that HDL particle profile measured by NMR spectroscopy should be considered to better stratify risk in population at high risk or in the setting of pharmacotherapy.
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Castaño D, Rattanasopa C, Monteiro-Cardoso VF, Corlianò M, Liu Y, Zhong S, Rusu M, Liehn EA, Singaraja RR. Lipid efflux mechanisms, relation to disease and potential therapeutic aspects. Adv Drug Deliv Rev 2020; 159:54-93. [PMID: 32423566 DOI: 10.1016/j.addr.2020.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023]
Abstract
Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired β-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.
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Zhu B, Feng Z, Guo Y, Zhang T, Mai A, Kang Z, Weijen T, Wang D, Yin D, Zhu D, Gao J. F0F1 ATP synthase regulates extracellular calcium influx in human neutrophils by interacting with Ca v2.3 and modulates neutrophil accumulation in the lipopolysaccharide-challenged lung. Cell Commun Signal 2020; 18:19. [PMID: 32019549 PMCID: PMC7001235 DOI: 10.1186/s12964-020-0515-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 01/17/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Neutrophils form the first line of innate host defense against invading microorganisms. We previously showed that F0F1 ATP synthase (F-ATPase), which is widely known as mitochondrial respiratory chain complex V, is expressed in the plasma membrane of human neutrophils and is involved in regulating cell migration. Whether F-ATPase performs cellular functions through other pathways remains unknown. METHODS Blue native polyacrylamide gel electrophoresis followed by nano-ESI-LC MS/MS identification and bioinformatic analysis were used to identify protein complexes containing F-ATPase. Then, the identified protein complexes containing F-ATPase were verified by immunoblotting, immunofluorescence colocalization, immunoprecipitation, real-time RT-PCR and agarose gel electrophoresis. Immunoblotting, flow cytometry and a LPS-induced mouse lung injury model were used to assess the effects of the F-ATPase-containing protein complex in vitro and in vivo. RESULTS We found that the voltage-gated calcium channel (VGCC) α2δ-1 subunit is a binding partner of cell surface F-ATPase in human neutrophils. Further investigation found that the physical connection between the two proteins may exist between the F1 part (α and β subunits) of F-ATPase and the α2 part of VGCC α2δ-1. Real-time RT-PCR and PCR analyses showed that Cav2.3 (R-type) is the primary type of VGCC expressed in human neutrophils. Research on the F-ATPase/Cav2.3 functional complex indicated that it can regulate extracellular Ca2+ influx, thereby modulating ERK1/2 phosphorylation and reactive oxygen species production, which are typical features of neutrophil activation. In addition, the inhibition of F-ATPase can reduce neutrophil accumulation in the lungs of mice that were intratracheally instilled with lipopolysaccharide, suggesting that the inhibition of F-ATPase may prevent neutrophilic inflammation-induced tissue damage. CONCLUSIONS In this study, we identified a mechanism by which neutrophil activity is modulated, with simultaneous regulation of neutrophil-mediated pulmonary damage. These results show that surface F-ATPase of neutrophils is a potential innate immune therapeutic target.
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Affiliation(s)
- Baoyi Zhu
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
| | - Zhengfu Feng
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
| | - Yan Guo
- Clinical Laboratory of Dongcheng People’s Hospital, Dong guan, 523007 Guangdong China
| | - Tian Zhang
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
| | - Ai Mai
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
| | - Zhanfang Kang
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
| | - Ting Weijen
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, 40402 Taiwan
| | - Dai Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics of Xiamen University, Xiamen, 361102 Fujian China
| | - Dazhong Yin
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
| | - Dongxing Zhu
- Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436 Guangdong China
| | - Jun Gao
- Department of Basic Medical Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511518 Guangdong China
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Su X, Peng D. The exchangeable apolipoproteins in lipid metabolism and obesity. Clin Chim Acta 2020; 503:128-135. [PMID: 31981585 DOI: 10.1016/j.cca.2020.01.015] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 12/29/2022]
Abstract
Dyslipidemia, characterized by increased plasma levels of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglyceride (TG), and reduced plasma levels of high-density lipoprotein cholesterol (HDL-C), is confirmed as a hallmark of obesity and cardiovascular diseases (CVD), posing serious risks to the future health of humans. Thus, it is important to understand the molecular metabolism of dyslipidemia, which could help reduce the morbidity and mortality of obesity and CVD. Currently, several exchangeable apolipoproteins, such as apolipoprotein A1 (ApoA1), apolipoprotein A5 (ApoA5), apolipoprotein E (ApoE), and apolipoprotein C3 (ApoC3), have been verified to exert vital effects on modulating lipid metabolism and homeostasis both in plasma and in cells, which consequently affect dyslipidemia. In the present review, we summarize the findings of the effect of exchangeable apolipoproteins on affecting lipid metabolism in adipocytes and hepatocytes. Furthermore, we also provide new insights into the mechanisms by which the exchangeable apolipoproteins influence the pathogenesis of dyslipidemia and its related cardio-metabolic disorders.
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Affiliation(s)
- Xin Su
- Department of Cardiovascular Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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Lee HJ, Moon J, Chung I, Chung JH, Park C, Lee JO, Han JA, Kang MJ, Yoo EH, Kwak SY, Jo G, Park W, Park J, Kim KM, Lim S, Ngoei KRW, Ling NXY, Oakhill JS, Galic S, Murray-Segal L, Kemp BE, Mantzoros CS, Krauss RM, Shin MJ, Kim HS. ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways. FASEB J 2019; 33:14825-14840. [PMID: 31670977 DOI: 10.1096/fj.201901440rr] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/17/2019] [Indexed: 12/11/2022]
Abstract
ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletal muscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake via AMPK in skeletal muscle cells and primary cultured myoblasts. Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibits ATP hydrolysis by β-F1-ATPase in plasma membrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose a mechanism by which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent.-Lee, H. J., Moon, J., Chung, I., Chung, J. H., Park, C., Lee, J. O., Han, J. A., Kang, M. J., Yoo, E. H., Kwak, S.-Y., Jo, G., Park, W., Park, J., Kim, K. M., Lim, S., Ngoei, K. R. W., Ling, N. X. Y., Oakhill, J. S., Galic, S., Murray-Segal, L., Kemp, B. E., Mantzoros, C. S., Krauss, R. M., Shin, M.-J., Kim, H. S. ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.
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Affiliation(s)
- Hye Jeong Lee
- Department of Anatomy, Korea University College of Medicine, Seoul, South Korea
| | - Jiyoung Moon
- Department of Public Health Sciences, Korea University, Seoul, South Korea
- Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - InHyeok Chung
- Department of Public Health Sciences, Korea University, Seoul, South Korea
| | - Ji Hyung Chung
- Department of Biotechnology, CHA University, Pocheon, South Korea
| | - Chan Park
- Department of Biotechnology, CHA University, Pocheon, South Korea
| | - Jung Ok Lee
- Department of Anatomy, Korea University College of Medicine, Seoul, South Korea
| | - Jeong Ah Han
- Department of Anatomy, Korea University College of Medicine, Seoul, South Korea
| | - Min Ju Kang
- Department of Anatomy, Korea University College of Medicine, Seoul, South Korea
| | - Eun Hye Yoo
- Department of Public Health Sciences, Korea University, Seoul, South Korea
| | - So-Young Kwak
- Department of Public Health Sciences, Korea University, Seoul, South Korea
| | - Garam Jo
- Department of Public Health Sciences, Korea University, Seoul, South Korea
| | - Wonil Park
- Department of Physical Education, Korea University, Seoul, South Korea
| | - Jonghoon Park
- Department of Physical Education, Korea University, Seoul, South Korea
| | - Kyoung Min Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Kevin R W Ngoei
- Protein Chemistry and Metabolism, University of Melbourne, Fitzroy, Victoria, Australia
| | - Naomi X Y Ling
- Metabolic Signaling Laboratory, St Vincenf's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia
| | - Jonathan S Oakhill
- Metabolic Signaling Laboratory, St Vincenf's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia
- Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia
| | - Sandra Galic
- Protein Chemistry and Metabolism, University of Melbourne, Fitzroy, Victoria, Australia
| | - Lisa Murray-Segal
- Protein Chemistry and Metabolism, University of Melbourne, Fitzroy, Victoria, Australia
| | - Bruce E Kemp
- Protein Chemistry and Metabolism, University of Melbourne, Fitzroy, Victoria, Australia
- Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia
| | - Christos S Mantzoros
- Division of Endocrinology, Beth-Israel Deaconess Medical Center-Harvard Medical School, Boston, Massachusetts, USA
| | - Ronald M Krauss
- Children's Hospital Oakland Research Institute, Oakland, California, USA
| | - Min-Jeong Shin
- Department of Public Health Sciences, Korea University, Seoul, South Korea
| | - Hyeon Soo Kim
- Department of Anatomy, Korea University College of Medicine, Seoul, South Korea
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Lorkowski SW, Brubaker G, Gulshan K, Smith JD. V-ATPase (Vacuolar ATPase) Activity Required for ABCA1 (ATP-Binding Cassette Protein A1)-Mediated Cholesterol Efflux. Arterioscler Thromb Vasc Biol 2019; 38:2615-2625. [PMID: 30354238 DOI: 10.1161/atvbaha.118.311814] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective- We have shown that ABCA1 (ATP-binding cassette protein A1) mediates unfolding of the apoA1 (apolipoprotein A1) N-terminal helical hairpin during apoA1 lipidation. Others have shown that an acidic pH exposes the hydrophobic surface of apoA1. We postulated that the V-ATPase (vacuolar ATPase) proton pump facilitates apoA1 unfolding and promotes ABCA1-mediated cholesterol efflux. Approach and Results- We found that V-ATPase inhibitors dose-dependently decreased ABCA1-mediated cholesterol efflux to apoA1 in baby hamster kidney cells and RAW264.7 cells; and similarly, siRNA knockdown of ATP6V0C inhibited ABCA1-mediated cholesterol efflux to apoA1 in RAW264.7 cells. Although ABCA1 expression did not alter total cellular levels of V-ATPase, ABCA1 increased the cell surface levels of the V0A1 and V1E1 subunits of V-ATPase. We generated a fluorescein isothiocyanate/Alexa647 double-labeled fluorescent ratiometric apoA1 pH indicator whose fluorescein isothiocyanate/Alexa647 emission ratio decreased as the pH drops. We found that ABCA1 induction in baby hamster kidney cells led to acidification of the cell-associated apoA1 pH indicator, compared with control cells without ABCA1 expression. The V-ATPase inhibitor bafilomycin A1 dose-dependently inhibited the apoA1 pH shift in ABCA1-expressing cells, without affecting the levels of cell-associated apoA1. However, we were not able to detect ABCA1-mediated extracellular proton release. We showed that acidic pH facilitated apoA1 unfolding, apoA1 solubilization of phosphatidycholine:phosphatidyserine liposomes, and increased lipid fluidity of these liposomes. Conclusions- Our results support a model that ABCA1 recruits V-ATPase to the plasma membrane where V-ATPase mediates apoA1 acidification and membrane remodeling that promote apoA1 unfolding and ABCA1-mediated HDL (high-density lipoprotein) biogenesis and lipid efflux.
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Affiliation(s)
- Shuhui Wang Lorkowski
- From the Department of Cellular and Molecular Medicine (S.W.L., G.B., K.G., J.D.S.), Cleveland Clinic, OH
| | - Gregory Brubaker
- From the Department of Cellular and Molecular Medicine (S.W.L., G.B., K.G., J.D.S.), Cleveland Clinic, OH
| | - Kailash Gulshan
- From the Department of Cellular and Molecular Medicine (S.W.L., G.B., K.G., J.D.S.), Cleveland Clinic, OH
| | - Jonathan D Smith
- From the Department of Cellular and Molecular Medicine (S.W.L., G.B., K.G., J.D.S.), Cleveland Clinic, OH.,Department of Cardiovascular Medicine (J.D.S.), Cleveland Clinic, OH
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Apolipoprotein A-I (ApoA-I), Immunity, Inflammation and Cancer. Cancers (Basel) 2019; 11:cancers11081097. [PMID: 31374929 PMCID: PMC6721368 DOI: 10.3390/cancers11081097] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 07/25/2019] [Accepted: 07/30/2019] [Indexed: 12/21/2022] Open
Abstract
Apolipoprotein A-I (ApoA-I), the major protein component of high-density lipoproteins (HDL) is a multifunctional protein, involved in cholesterol traffic and inflammatory and immune response regulation. Many studies revealing alterations of ApoA-I during the development and progression of various types of cancer suggest that serum ApoA-I levels may represent a useful biomarker contributing to better estimation of cancer risk, early cancer diagnosis, follow up, and prognosis stratification of cancer patients. In addition, recent in vitro and animal studies disclose a more direct, tumor suppressive role of ApoA-I in cancer pathogenesis, which involves anti-inflammatory and immune-modulatory mechanisms. Herein, we review recent epidemiologic, clinicopathologic, and mechanistic studies investigating the role of ApoA-I in cancer biology, which suggest that enhancing the tumor suppressive activity of ApoA-I may contribute to better cancer prevention and treatment.
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Cabou C, Honorato P, Briceño L, Ghezali L, Duparc T, León M, Combes G, Frayssinhes L, Fournel A, Abot A, Masri B, Parada N, Aguilera V, Aguayo C, Knauf C, González M, Radojkovic C, Martinez LO. Pharmacological inhibition of the F 1 -ATPase/P2Y 1 pathway suppresses the effect of apolipoprotein A1 on endothelial nitric oxide synthesis and vasorelaxation. Acta Physiol (Oxf) 2019; 226:e13268. [PMID: 30821416 DOI: 10.1111/apha.13268] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 02/14/2019] [Accepted: 02/22/2019] [Indexed: 12/12/2022]
Abstract
AIM The contribution of apolipoprotein A1 (APOA1), the major apolipoprotein of high-density lipoprotein (HDL), to endothelium-dependent vasodilatation is unclear, and there is little information regarding endothelial receptors involved in this effect. Ecto-F1 -ATPase is a receptor for APOA1, and its activity in endothelial cells is coupled to adenosine diphosphate (ADP)-sensitive P2Y receptors (P2Y ADP receptors). Ecto-F1 -ATPase is involved in APOA1-mediated cell proliferation and HDL transcytosis. Here, we investigated the effect of lipid-free APOA1 and the involvement of ecto-F1 -ATPase and P2Y ADP receptors on nitric oxide (NO) synthesis and the regulation of vascular tone. METHOD Nitric oxide synthesis was assessed in human endothelial cells from umbilical veins (HUVECs) and isolated mouse aortas. Changes in vascular tone were evaluated by isometric force measurements in isolated human umbilical and placental veins and by assessing femoral artery blood flow in conscious mice. RESULTS Physiological concentrations of lipid-free APOA1 enhanced endothelial NO synthesis, which was abolished by inhibitors of endothelial nitric oxide synthase (eNOS) and of the ecto-F1 -ATPase/P2Y1 axis. Accordingly, APOA1 inhibited vasoconstriction induced by thromboxane A2 receptor agonist and increased femoral artery blood flow in mice. These effects were blunted by inhibitors of eNOS, ecto-F1 -ATPase and P2Y1 receptor. CONCLUSIONS Using a pharmacological approach, we thus found that APOA1 promotes endothelial NO production and thereby controls vascular tone in a process that requires activation of the ecto-F1 -ATPase/P2Y1 pathway by APOA1. Pharmacological targeting of this pathway with respect to vascular diseases should be explored.
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Affiliation(s)
- Cendrine Cabou
- INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases University of Toulouse, Paul Sabatier University Toulouse France
- Department of Human Physiology, Faculty of Pharmacy University Paul Sabatier Toulouse France
| | - Paula Honorato
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy Universidad de Concepción Concepción Chile
| | - Luis Briceño
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy Universidad de Concepción Concepción Chile
| | - Lamia Ghezali
- INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases University of Toulouse, Paul Sabatier University Toulouse France
| | - Thibaut Duparc
- INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases University of Toulouse, Paul Sabatier University Toulouse France
| | - Marcelo León
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy Universidad de Concepción Concepción Chile
| | - Guillaume Combes
- INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases University of Toulouse, Paul Sabatier University Toulouse France
| | - Laure Frayssinhes
- INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases University of Toulouse, Paul Sabatier University Toulouse France
| | - Audren Fournel
- UMR 1220, IRSD, INSERM, INRA, ENVT, European Associated Laboratory NeuroMicrobiota (INSERM/UCL) University of Toulouse Toulouse France
| | - Anne Abot
- UMR 1220, IRSD, INSERM, INRA, ENVT, European Associated Laboratory NeuroMicrobiota (INSERM/UCL) University of Toulouse Toulouse France
| | - Bernard Masri
- INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases University of Toulouse, Paul Sabatier University Toulouse France
| | - Nicol Parada
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy Universidad de Concepción Concepción Chile
| | - Valeria Aguilera
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy Universidad de Concepción Concepción Chile
| | - Claudio Aguayo
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy Universidad de Concepción Concepción Chile
- Group of Research and Innovation in Vascular Health (GRIVAS Health) Chillan Chile
| | - Claude Knauf
- UMR 1220, IRSD, INSERM, INRA, ENVT, European Associated Laboratory NeuroMicrobiota (INSERM/UCL) University of Toulouse Toulouse France
| | - Marcelo González
- Group of Research and Innovation in Vascular Health (GRIVAS Health) Chillan Chile
- Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, and Department of Obstetrics and Gynecology, Faculty of Medicine Universidad de Concepción Concepción Chile
| | - Claudia Radojkovic
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy Universidad de Concepción Concepción Chile
| | - Laurent O. Martinez
- INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases University of Toulouse, Paul Sabatier University Toulouse France
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Speransky S, Serafini P, Caroli J, Bicciato S, Lippman ME, Bishopric NH. A novel RNA aptamer identifies plasma membrane ATP synthase beta subunit as an early marker and therapeutic target in aggressive cancer. Breast Cancer Res Treat 2019; 176:271-289. [PMID: 31006104 PMCID: PMC6555781 DOI: 10.1007/s10549-019-05174-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 02/18/2019] [Indexed: 12/22/2022]
Abstract
PURPOSE Primary breast and prostate cancers can be cured, but metastatic disease cannot. Identifying cell factors that predict metastatic potential could guide both prognosis and treatment. METHODS We used Cell-SELEX to screen an RNA aptamer library for differential binding to prostate cancer cell lines with high vs. low metastatic potential. Mass spectroscopy, immunoblot, and immunohistochemistry were used to identify and validate aptamer targets. Aptamer properties were tested in vitro, in xenograft models, and in clinical biopsies. Gene expression datasets were queried for target associations in cancer. RESULTS We identified a novel aptamer (Apt63) that binds to the beta subunit of F1Fo ATP synthase (ATP5B), present on the plasma membrane of certain normal and cancer cells. Apt63 bound to plasma membranes of multiple aggressive breast and prostate cell lines, but not to normal breast and prostate epithelial cells, and weakly or not at all to non-metastasizing cancer cells; binding led to rapid cell death. A single intravenous injection of Apt63 induced rapid, tumor cell-selective binding and cytotoxicity in MDA-MB-231 xenograft tumors, associated with endonuclease G nuclear translocation and DNA fragmentation. Apt63 was not toxic to non-transformed epithelial cells in vitro or adjacent normal tissue in vivo. In breast cancer tissue arrays, plasma membrane staining with Apt63 correlated with tumor stage (p < 0.0001, n = 416) and was independent of other cancer markers. Across multiple datasets, ATP5B expression was significantly increased relative to normal tissue, and negatively correlated with metastasis-free (p = 0.0063, 0.00039, respectively) and overall (p = 0.050, 0.0198) survival. CONCLUSION Ecto-ATP5B binding by Apt63 may disrupt an essential survival mechanism in a subset of tumors with high metastatic potential, and defines a novel category of cancers with potential vulnerability to ATP5B-targeted therapy. Apt63 is a unique tool for elucidating the function of surface ATP synthase, and potentially for predicting and treating metastatic breast and prostate cancer.
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Affiliation(s)
- S Speransky
- Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USA
| | - P Serafini
- Department of Microbiology & Immunology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USA
| | - J Caroli
- Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - S Bicciato
- Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - M E Lippman
- Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USA
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - N H Bishopric
- Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USA.
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
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